Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma

Patrick J. Grohar; Suntae Kim; Guillermo O. Rangel Rivera; Nirmalya Sen; Sara Haddock; Matt L. Harlow; Nichole K. Maloney; Jack Zhu; Maura O'Neill; Tamara L. Jones; Konrad Huppi; Magdalena Grandin; Kristen Gehlhaus; Carleen A. Klumpp-Thomas; Eugen Buehler; Lee J. Helman; Scott E. Martin; Natasha J. Caplen

doi:10.1016/j.celrep.2015.12.063

Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma

Patrick J. Grohar, Suntae Kim, Guillermo O. Rangel Rivera, Nirmalya Sen, Sara Haddock, Matt L. Harlow, Nichole K. Maloney, Jack Zhu, Maura O'Neill, Tamara L. Jones, Konrad Huppi, Magdalena Grandin, Kristen Gehlhaus, Carleen A. Klumpp-Thomas, Eugen Buehler, Lee J. Helman, Scott E. Martin, Natasha J. Caplen

School of Medicine

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16 Scopus citations

Abstract

Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.

Original language	English (US)
Pages (from-to)	598-610
Number of pages	13
Journal	Cell Reports
Volume	14
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2015.12.063
State	Published - Jan 26 2016

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Grohar, P. J., Kim, S., Rangel Rivera, G. O., Sen, N., Haddock, S., Harlow, M. L., Maloney, N. K., Zhu, J., O'Neill, M., Jones, T. L., Huppi, K., Grandin, M., Gehlhaus, K., Klumpp-Thomas, C. A., Buehler, E., Helman, L. J., Martin, S. E., & Caplen, N. J. (2016). Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma. Cell Reports, 14(3), 598-610. https://doi.org/10.1016/j.celrep.2015.12.063

Grohar, PJ, Kim, S, Rangel Rivera, GO, Sen, N, Haddock, S, Harlow, ML, Maloney, NK, Zhu, J, O'Neill, M, Jones, TL, Huppi, K, Grandin, M, Gehlhaus, K, Klumpp-Thomas, CA, Buehler, E, Helman, LJ, Martin, SE & Caplen, NJ 2016, 'Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma', Cell Reports, vol. 14, no. 3, pp. 598-610. https://doi.org/10.1016/j.celrep.2015.12.063

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title = "Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma",

abstract = "Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.",

author = "Grohar, {Patrick J.} and Suntae Kim and {Rangel Rivera}, {Guillermo O.} and Nirmalya Sen and Sara Haddock and Harlow, {Matt L.} and Maloney, {Nichole K.} and Jack Zhu and Maura O'Neill and Jones, {Tamara L.} and Konrad Huppi and Magdalena Grandin and Kristen Gehlhaus and Klumpp-Thomas, {Carleen A.} and Eugen Buehler and Helman, {Lee J.} and Martin, {Scott E.} and Caplen, {Natasha J.}",

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AU - Grohar, Patrick J.

AU - Kim, Suntae

AU - Rangel Rivera, Guillermo O.

AU - Sen, Nirmalya

AU - Haddock, Sara

AU - Harlow, Matt L.

AU - Maloney, Nichole K.

AU - Zhu, Jack

AU - O'Neill, Maura

AU - Jones, Tamara L.

AU - Huppi, Konrad

AU - Grandin, Magdalena

AU - Gehlhaus, Kristen

AU - Klumpp-Thomas, Carleen A.

AU - Buehler, Eugen

AU - Helman, Lee J.

AU - Martin, Scott E.

AU - Caplen, Natasha J.

PY - 2016/1/26

Y1 - 2016/1/26

N2 - Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.

AB - Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.

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Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma

Abstract

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